Thiazolobenzoheterocycle derivatives are described by A. RICHARDSON, J. Org. Chem., 28, 2581-87 (1963) but no pharmacological activity is mentioned for these products.
The present invention relates to compounds of formula: 
their salts, processes for preparing them and the medicaments containing them.
In formula (I),
R1 represents a sulphur or selenium atom,
R2 represents a hydrogen atom or an alkyl radical,
xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH(R7) xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94, xe2x80x94CH2xe2x80x94CH(R9)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x80x94Sxe2x80x94, xe2x80x94CHxe2x80x94CH2xe2x80x94SOxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94SO2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Sexe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R10)xe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94N(R10)xe2x80x94, xe2x80x94CH2xe2x80x94CF2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CF2xe2x80x94CH(OH)xe2x80x94, xe2x80x94CH2xe2x80x94CH(R13)xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94CH(R13)xe2x80x94SOxe2x80x94 or xe2x80x94CH2xe2x80x94CH(R13)xe2x80x94SO2xe2x80x94,
R6 represents a polyfluoroalkyl, polyfluoroalkoxy or polyfluoroalkylthio radical,
R7 represents an alkyl, xe2x80x94CH2OH, xe2x80x94CH2xe2x80x94SO2-alk or xe2x80x94CH2xe2x80x94NR11R12 radical,
R8 represents a radical alkyl, hydroxyl, xe2x80x94CH2OH, xe2x80x94NR11R12, xe2x80x94CH2xe2x80x94NR11R12, xe2x80x94S-alk, xe2x80x94SO-alk, xe2x80x94SO2-alk, thienyl, furyl, phenyl or phenyl substituted with a substituent chosen from halogen atoms and alkyl and alkoxy radicals,
R9 represents an alkyl or xe2x80x94CH2OH radical,
R10 represents a hydrogen atom or an alkyl radical,
R11 represents a hydrogen atom or an alkyl, xe2x80x94CO-alk or xe2x80x94COxe2x80x94CF3 radical,
R12 represents a hydrogen atom or an alkyl radical, or alternatively R11 and R12 form with the nitrogen atom to which they are attached a saturated or unsaturated 5- or 6-membered heterocycle optionally containing another heteroatom chosen from nitrogen, oxygen and sulphur, this heterocycle being unsubstituted or substituted with one or more substituents chosen from alkyl, phenyl, halophenyl and phenylalkyl radicals,
R13 represents an alkyl or xe2x80x94CH2OH radical, alk represents an alkyl radical.
In the preceding definitions and in those which will be given hereinafter, unless otherwise indicated, the alkyl an d alkoxy radicals and portions contain 1 to 6 straight- or branched-chain carbon atoms and the halogen atoms are bromine chlorine, fluorine and iodine atoms.
Among the polyfluoroalkyl radicals, there may be mentioned the trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, perfluoroethyl, perfluoropropyl and perfluorobutyl radicals.
Among the polyfluoroalkoxy radicals, there may be mentioned the trifluoromethoxy, perfluoroethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,3,3,3-pentafluoropropoxy, perfluoropropoxy and perfluorobutoxy radicals.
Among the polyfluoroalkylthio radicals, there may be mentioned the trifluoromethylthic, perfluoroethylthio and perfluoropropylthio radicals.
The preferred polyfluoroalkyl, polyfluoroalkoxy and polyfluoroalkylthio radicals are trifluoromethyl, trifluoromethpxy, pentafluoroethoxy and trifluoromethylthio radicals.
As saturated or unsaturated 5- or 6-membered heterocycle optionally containing another heteroatom chosen from nitrogen, oxygen and sulphur, there may be mentioned pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine, these heterocycles being unsubstituted or substituted with an alkyl, phenyl, halophenyl or phenylalkyl radical.
The invention also relates to the addition salts of the compounds of formula (I) with inorganic or organic acids.
The compounds of formula (I) which contain one or more asymmetric centres have isomeric forms; these isomers and mixtures form part of the invention. The racemates and the enantiomers of these compounds also form part of the invention.
The compounds of formula (I) for which R1 represents a sulphur or selenium atom, R2 represents a hydrogen atom, xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH(R7)xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94, xe2x80x94CH2xe2x80x94CH(R9)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Sexe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R10)xe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94N(R10)xe2x80x94, xe2x80x94CH2xe2x80x94CF2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CF2xe2x80x94CH(OH)xe2x80x94, xe2x80x94CH2xe2x80x94CH(R13)xe2x80x94Sxe2x80x94, with the proviso that R8 does not represent a hydroxyl radical, may be prepared by reacting an alkali metal thiocyanate or an alkali metal selenocyanate with a derivative of formula: 
in which R6 has the same meanings as in formula (I),
xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH(R7)xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2CH(R8)xe2x80x94, xe2x80x94CH2xe2x80x94CH(R9)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Sexe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R10)xe2x80x94, xe2x80x94CH2xe2x80x94CF2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CF2xe2x80x94CH(OH)xe2x80x94, xe2x80x94CH2xe2x80x94CH(R13)xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94N(R10)xe2x80x94 in which R7, R8, R9, R10 and R13 have the same meanings as in formula (I) with the proviso that R8 does not represent a hydroxyl radical.
This reaction is generally carried out in the presence of bromine, chlorine, chloramide and copper(II) chloride, in an organic solvent such as acetic acid, at a temperature between 15xc2x0 C. and the boiling point of the reaction medium. As alkali metal thiocyanate, it is preferable to use potassium thiocyanate. As alkali metal selenocyanate, it is preferable to use potassium selenocyanate.
The derivatives of formula (II), with the exception of 6-trifluoromethyl 1,2,3,4-tetrahydroquinoline, 2-methyl-6-trifluoromethoxy-1,2,3,4-tetrahydroquinoline, 6-trifluoromethyl-1,2,3,4-tetrahydroquinoxaline and 2-oxo-7-trifluoromethyl-3,4-dihydroquinoxaline, are new and, as such, form part of the invention.
The compounds of formula (I) for which R2 represents an alkyl radical may be prepared by alkylation of a corresponding compound of formula (I) for which R2 represents a hydrogen atom.
This alkylation is carried out by any method which makes it possible to alkylate an imine functional group. Preferably, the procedure is carried out by means of a derivative Ra-X in which Ra represents an alkyl radical and X represents a reactive group such as a halogen atom (preferably chlorine, bromine or iodine) or a tosyloxy radical, in an in,ert organic solvent such as a lower aliphatic alcohol (ethanol, propanol or butanol for example), a ketone (acetone or methyl ethyl ketone for example) or dimethylformamide, in the presence of a base such as an alkali metal carbonate (potassium carbonate for example), at a temperature between 20xc2x0 C. and the boiling point of the reaction medium.
The compounds of formula (I) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94 and R8 represents a hydroxyl radical may be obtained by reducing a corresponding compound of formula (I) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94.
This reaction is carried out by any method which makes it possible to pass from a ketone to an alcohol. The procedure is generally carried out by means of sodium borohydride, in an alcohol such as methanol or ethanol, at a temperature of between 0 and 25xc2x0 C.
The compounds of formula (I) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94SOxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94SO2xe2x80x94, xe2x80x94CH2xe2x80x94CH(R13) xe2x80x94SOxe2x80x94 or xe2x80x94CH2xe2x80x94CH(R13)xe2x80x94SO2 may be prepared by oxidizing a corresponding compound of formula (I) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Sexe2x80x94 or xe2x80x94CH2xe2x80x94CH(R13)xe2x80x94Sxe2x80x94.
This oxidation is carried out according to known methods of oxidizing sulphur-containing derivatives as described by M. HUDLICKY, Oxidations in Organic Chemistry, ACS Monograph, 186, 252-263 (1990). For example, the procedure is carried out by the action of an organic peracid or a salt of such an acid (percarboxylic or persulphonic acid, in particular perbenzoic acid, 3-chloroperbenzoic acid, 4-nitroperbenzoic acid, peracetic acid, pertrifluoroacetic acid, performic acid or monoperphthalic acid) or inorganic peracids or a salt of such an acid (for example periodic or persulphuric acid), in an inert solvent such as a chlorinated solvent (chloroform or dichloromethane for example), at a temperature of between 0 and 25xc2x0 C. It is also possible to use hydrogen peroxide and a periodate (sodium periodate for example), in an inert solvent such as a lower aliphatic alcohol, water or a mixture of these solvents, at a temperature of between 0 and 20xc2x0 C. It is also possible to carry out the procedure by means of tert-butyl hydroperoxide in the presence of titanium tetraisopropoxide or oxone(copyright) (potassium peroxymono-sulphate) in a lower aliphatic alcohol or a water-alcohol mixture, at a temperature close to 25xc2x0 C.
The compounds of formula (I) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH(R7)xe2x80x94CH2xe2x80x94CH2xe2x80x94 in which R7 represents a radical xe2x80x94CH2xe2x80x94NR11R12 and R2 represents a hydrogen atom may be prepared by reacting an amine HNR11R12 for which R11 and R12 have the same meanings as in formula (I) with a derivative of formula: 
in which R1 and R6 have the same meanings as in formula (I) followed by hydrolysis to release the imine.
This reaction is generally carried out in an inert solvent such as a chlorinated solvent (chloroform or dichloromethane for example), at a temperature of between 0 and 50xc2x0 C. The hydrolysis is preferably carried out by means of an alkali metal carbonate (potassium carbonate for example), in an aqueous-alcoholic medium, at a temperature close to 20xc2x0 C.
The derivatives of formula (III) may be obtained from the corresponding compounds of formula (I) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH(R7)xe2x80x94CH2xe2x80x94CH2xe2x80x94 in which R7 represents a radical xe2x80x94CH2OH and R2 represents a hydrogen atom according to the following reaction scheme: 
In these formulae, R1 and R6 have the same meanings as in formula (I).
The derivatives of formula (II) for which R6 has the same meanings as in formula (I) and xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH(R7)xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94, xe2x80x94CH2xe2x80x94CH(R9)xe2x80x94CH2xe2x80x94, R7 represents an alkyl, xe2x80x94CH2OH, xe2x80x94CH2xe2x80x94NR11R12 or xe2x80x94CH2xe2x80x94SO2-alk radical, R8 represents an alkyl or xe2x80x94CH2xe2x80x94NR11R12 radical and R9 represents an alkyl radical may be obtained by hydrogenation of a derivative of formula: 
in which R6 has the same meanings as in formula (I) and xe2x95x90R3xe2x80x94R4xe2x95x90R5xe2x80x94 represents a chain of formula xe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x95x90C(R7)xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x95x90CHxe2x80x94CHxe2x95x90C(R8)xe2x80x94, xe2x95x90CHxe2x80x94C(R9)xe2x95x90CHxe2x80x94, R7 represents an alkyl, xe2x80x94CH2OH, xe2x80x94CH2xe2x80x94NR11R12 or xe2x80x94CH2xe2x80x94SO2-alk radical, R8 represents an alkyl or xe2x80x94CH2xe2x80x94NR11R12 radical, R9 represents an alkyl radical, R11 and R12 have the same meanings as in formula (I).
This hydrogenation is generally carried out either by means of hydrogen, at a pressure of 2 to 12 bar, in an inert organic solvent such as a lower aliphatic alcohol (methanol or ethanol for example) or tetrahydrofuran or a mixture of these solents, in the presence of a hydrogenation catalyst such as platinum oxide, at a temperature close to 20xc2x0 C., or by means of reducing agents such as sodium borohydride in the presence of nickel chloride or sodium cyanoborohydride, in an alcohol (methanol or ethanol for example), at a temperature close to 20xc2x0 C.
The derivatives of formula (IV) for which xe2x95x90R3xe2x80x94R4xe2x95x90R5xe2x80x94 represents a chain of formula xe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x95x90C(R7)xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x95x90CHxe2x80x94C(R9)xe2x95x90CHxe2x80x94, R7 represents an alkyl radical and R9 represents an alkyl radical may be obtained from a 4-polyfluoroalkylaniline, 4-polyfluoroalkoxyaniline or 4-polyfluoroalkylthioaniline by application or adaptation of the methods described in the examples and of the method""s described by G. JONES, Heterocyclic compounds, Quinolines, 32, part 1, Interscience, 93-318 (1977); J. Pharm. Sci., 68 (3), 336-8 (1979).
4-Polyfluoroalkylanilline, 4-polyfluoroalkoxyaniline and 4-polyfluoroalkylthioaniline are commercially available or may be obtained by application or adaptation of the methods described in J. Org.Chem., 29, 1 (1964), and in patents U.S. Pat. No. 3,920,444, U.S. Pat. No. 2,436,100, DE 2,606,982, EP 205821 and EP 546391.
The derivatives of formula (IV) for which xe2x95x90R3xe2x80x94R4xe2x95x90R5xe2x80x94 represents a chain of formula xe2x95x90C(R7)xe2x80x94CHxe2x95x90CHxe2x80x94 in which R7 represents a radical xe2x80x94CH2xe2x80x94NR11R12 may be obtained from a corresponding 2-methyl-6-polyfluoroalkylquinoline or 2-methyl-6-polyfluoroalkoxyquinoline or 2-methyl-6-polyfluoroalkylthioquinoline according to the following reaction scheme: 
In these formulae, R6, R11 and R12 have the same meanings as in formula (I).
The derivatives of formula (IV) for which R6 has the same meanings as in formula (I) and xe2x95x90R3xe2x80x94R4xe2x95x90R5xe2x80x94 represents a chain of formula xe2x95x90C(R7)xe2x80x94CHxe2x95x90CHxe2x80x94, R7 represents a radical xe2x80x94CH2OH may be obtained by reacting acetic anhydride with 2-methyl-6-polyfluoroalkylquinoline 1-oxide or 2-methyl-6-polyfluoroalkoxyquinoline 1-oxide or 2-methyl-6-polyfluoroalkylthioquinoline 1-oxide at the boiling point of the reaction medium, followed by hydrolysis, for example, by the action of a dilute solution of an alkali metal hydroxide, in a solvent such as a water-dioxane mixture, at the boiling point of the reaction medium.
The derivatives of formula (IV) for which xe2x95x90R3xe2x80x94R4xe2x95x90R5xe2x80x94 represents a chain of formula xe2x95x90C(R7)xe2x80x94CHxe2x95x90CHxe2x80x94 and R7 represents a radical xe2x80x94CH2xe2x80x94SO2-alk may be obtained by reacting a 6-polyfluoroalkylquinoline 1-oxide, 6-polyfluoroalkoxyquinoline 1-oxide or 6-polyfluoroalkylthioquinoline 1-oxide and acetic anhydride with a derivative alk-SO2xe2x80x94CH2xe2x80x94COCH3 in which alk represents an alkyl radical, in ethylene glycol dimethyl ether, at a temperature varying from 0 to 80xc2x0 C.
2-Methyl-6-polyfluoroalkylquinoline 1-oxide, 2-methyl-6-polyfluoroalkoxyquinoline 1-oxide or 2-methyl-6-polyfluoroalkylthioquinoline 1-oxide and 6-polyfluoroalkylquinoline 1-oxide, 6-polyfluoroalkoxyquinoline 1-oxide or 6-polyfluoroalkylthioquinoline 1-oxide may be obtained by oxidizing the corresponding quinolines, by means of an oxidizing agent such as 3-chloroperbenzoic acid, in an inert organic solvent such as a chlorinated solvent (chloroform or dichloromethane for example), at a temperature close to 20xc2x0 C.
The derivatives of formula (IV) for which xe2x95x90R3xe2x80x94R4xe2x95x90R5xe2x80x94 represents a chain of formula xe2x95x90C(R7)xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x95x90CHxe2x80x94CHxe2x95x90C(R8)xe2x80x94 and R7 and R8 represent xe2x80x94CH2xe2x80x94NR11R12 radicals may be obtained by reacting an amine HNR11R12 in which R11 and R12 have the same meanings as in formula (I) with a corresponding derivative of formula (IV) for which xe2x95x90R3xe2x80x94R4xe2x95x90R5xe2x80x94 represents a chain of formula xe2x95x90C(R7)xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x95x90CHxe2x80x94CHxe2x95x90C(R8)xe2x80x94 and R7 and R8 represent xe2x80x94CH2OH radicals in the form of a reactive derivative.
This reaction is generally carried out in an inert organic solvent such as an ether (tetrahydrofuran or dioxane for example), a chlorinated solvent (chloroform for example), in the presence of a base, at a temperature between 20xc2x0 C. and the boiling point of the reaction medium. As a reactive derivative, chloride, tosylate or mesylate may be mentioned.
The derivatives of formula (IV) for which xe2x95x90R3xe2x80x94R4xe2x95x90R5xe2x80x94 represents a chain of formula xe2x95x90CHxe2x80x94CHxe2x95x90C(R8)xe2x80x94 and R8 represents an alkyl radical may be obtained by application or adaptation of the method described by KRAINER et al., Chem. Heterocycl. Compd. 9, 217-219 (1973) or Khim. Geterotsikl. Soedin., 9 (2), 235-238 (1973).
The derivatives of fo rmula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94 and R8 represents a radical xe2x80x94CH2xe2x80x94OH, thienyl, furyl, phenyl or phenyl substituted with a substituent chosen from halogen atoms and alkyl or alkoxy radicals or xe2x80x94NR11R12 in which R11 and R12 represent hydrogen atoms or R11 represents a radical xe2x80x94CO-alk and R12 represents an alkyl radical or R11 represents a hydrogen atom and R12 represents an alkyl radical or R11 and R12 form with the nitrogen atom to which they are attached a saturated or unsaturated 5- or 6-membered heterocycle optionally containing another heteroatom chosen from nitrogen, oxygen.and sulphur and optionally substituted with an alkyl, phenyl, halophenyl or ph,enylalkyl radical may be obtained by reacting a derivative of formula: 
in which R6 has the same meanings as in formula (I) with a derivative Rbxe2x80x94CHxe2x95x90CH2 for which Rb represents a radical xe2x80x94CH2xe2x80x94OH, thienyl, furyl, phenyl or phenyl substituted with a substituent chosen from halogen atoms and alkyl and alkoxy radicals or xe2x80x94NR11R12 in which either R11 and R12 form with the nitrogen atom to which they are attached a phthalimido radical followed by hydrolysis in order to obtain the derivative for which R11 and R12 are hydrogen atoms, or R11 represents a radical xe2x80x94CO-alk and R12 represents an alkyl radical optionally followed by hydrolysis in order to obtain the derivatives for which R11 represents a hydrogen atom and R12 represents an alkyl radical, or R11 and R12 form with the nitrogen atom to which they are attached a saturated or unsaturated 5- or 6-membered heterocycle optionally containing another heteroatom chosen from nitrogen, oxygen and sulphur and optionally substituted with an alkyl, phenyl, halophenyl or phenylalkyl radical.
This reaction is generally carried out in an inert organic solvent such as a chlorinated solvent (chloroform or dichloromethane for example), in the presence of a Lewis acid such as tin tetrachloride, titanium tetrachloride, boron trifluoride etherate, at a temperature varying from xe2x88x9280xc2x0 C. to a temperature close to 20xc2x0 C. The hydrolysis of the phthalimido and of the acylated derivative is generally carried out by means of an acid such as hydrochloric acid, in an aqueous medium, at a temperature between 20xc2x0 C. and the boiling point of the reaction medium.
The derivatives of formula (V) may be obtained by the action of formaldehyde and sodium p-toluenesulphinate and then of a 4-polyfluoroalkylaniline, 4-polyfluoroalkoxyaniline or 4-polyfluoroalkylthioaniline, in an aqueous medium, in the presence of hydrochloric acid, at a temperature close to 25xc2x0 C.
The Rbxe2x80x94CHxe2x95x90CH2 derivatives are commercially available or may be obtained by application or adaptation of the methods described by ABARCA et al., Tetrahedron, 43 (1), 269-274 (1987); NEGISHI et al., Heterocycles, 18 spec. Issue, 117-22 (1982); REIJENDAM et al., Tetrahedron, 26, 1291 (1970); HACHIHAMA et al., Chem. Abstr., 44, 9720f (1950); TAGAKI et al., Tetrahedron Lett., 2587 (1974); Chem. Abstr., 65, 18503e (1966); Chem. Abstr., 71, 49326r (1969); Chem. Abstr., 63, 18119f (1965) and Chem. Abstr., 58, 8083b.
The derivatives of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94 and R8 represents a radical xe2x80x94NR11R12 in which R11 represents a hydrogen atom and R12 represents a radical xe2x80x94CO-alk may be obtained by acylation of a corresponding derivative of formula (II) for which R11 and R12 represent hydrogen atoms.
This reaction is generally carried out by means of an acyl halide and, in particular, of an acyl chloride or bromide, in an inert solvent such as tetrahydrofuran, at a temperature between 20xc2x0 C. and the boiling point of the reaction medium.
The derivatives of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94 and R8 represents a radical xe2x80x94NR11R12 in which R11 represents an alkyl radical (2-6C) and R12 represents an alkyl radical may be obtained by reducing a corresponding derivative of formula (II) for which R12 represents an alkyl radical and R11 represents a radical xe2x80x94CO-alk.
This reduction is generally carried out by means of the borane-methyl sulphide complex, in tetrahydrofuran, at a temperature close to 20xc2x0 C.
The derivatives of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94 in which R8 represents a radical xe2x80x94NR11R12 for which R11 and R12 form with the nitrogen atom to which they are attached pyrrolidine, morpholine, piperidine or piperazine may also be obtained by reducing a derivative of formula: 
in which Rc represents a 2-oxopyrrolidin-1-yl, 3-oxomorpholin-4-yl, 2-oxopiperidin-1-yl or 2-oxopiperazin-1-yl and R6 has the same meanings as in formula (I).
This reduction is generally carried out by means of the borane-methyl sulphide complex, in tetrahydrofuran, at a temperature close to 20xc2x0 C.
The derivatives of formula (VI) are themselves obtained according to the process mentioned above from a derivative of formula (V) and from a derivative Rbxe2x80x94CHxe2x95x90CH2 for which Rb represents a 2-oxopyrrolidin-1-yl, 3-oxomorpholin-4-yl, 2-oxopiperidin-1-yl or 2-oxopiperazin-1-yl radical.
The derivatives of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94 in which R8 represents a radical xe2x80x94NR11R12, R12 represents a hydrogen atom or an alkyl radical and R11 represents a radical xe2x80x94COxe2x80x94CF3 may be obtained by reacting trifluoroacetic anhydride with aicorresponding derivative of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94 in which R8 represents a radical xe2x80x94NR11R12, R12 represents a hydrogen atom or an alkyl radical and R11 represents a hydrogen atom.
This reaction is generally carried out in pyridine, at a temperature close to xe2x88x9230xc2x0 C.
The derivatives of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain.of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94 in which R8 represents a radical xe2x80x94NR11R12 or xe2x80x94S-alk may be obtained by reacting a derivative HR8 for which R8 represents a radical xe2x80x94NR11R12 or xe2x80x94S-alk, R11, R12 and alk having the same meanings as in formula (I) with a derivative of formula: 
in which R6 has the same meanings as in formula (I), Hal represents a halogen atom and preferably a chlorine or bromine atom and Re represents a tert-butyl radical followed by deprotection of the cyclic nitrogen.
When R8 represents a radical xe2x80x94NR11R12, this reaction is generally carried out in an alcohol (ethanol, methanol for example), at a temperature close to 20xc2x0 C. When R8 represents a radical xe2x80x94S-alk, this reaction is generally carried out in dimethylformamide, in the presence of an alkali metal hydride (preferably sodium hydride), at a temperature of between 0 and 25xc2x0 C. The deprotection is preferably carried out by means of trifluoroacetic acid, in dichloromethane, at a temperature close to 20xc2x0 C.
The derivatives of formula (VII) may be obtained by halogenation of a corresponding tert-butyl 6-polyfluoroalkyl-1,2,3,4-tetrahydroquinoline-1-carboxylate or tert-butyl 6-polyfluoroalkoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate or tert-butyl 6-polyfluoroalkylthio-1,2,3,4-tetrahydroquinoline-1-carboxylate.
This halogenation is carried out by any method known to persons skilled in the art which does not modify the remainder of the molecule. For example, it is possible to brominate by means of N-bromosuccinimide, in an inert solvent such as a chlorinated solvent such as carbon tetrachloride, in the presence of benzoyl peroxide, at a temperature close to 20xc2x0 C.
The derivatives of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of, formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94 in which R8 represents a radical xe2x80x94SO-alk or xe2x80x94SO2-alk may be obtained by oxidizing a corresponding derivative of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94 in which R8 represents a radical xe2x80x94S-alk.
This oxidation is carried out as mentioned above for the preparation of the compounds of formula (I) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94SOxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94SO2, xe2x80x94CH2xe2x80x94CH(R13)xe2x80x94SOxe2x80x94 or xe2x80x94CH2xe2x80x94CH(R13)xe2x80x94SO2xe2x80x94.
The derivatives of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94CH2-Se or xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R10)xe2x80x94 may be obtained by reducing a derivative of formula: 
in which Rd represents an oxygen, sulphur or selenium atom or N(R10) and R6 and R10 have the same meanings as in formula (I).
This reaction is carried out by means of a reducing agent such as lithium tetrahydroaluminate, in an inert organic solvent such as, tetrahydrofuran, at a temperature close to 20xc2x0 C.
The derivatives of formula (VIII) may be obtained from a derivative of formula: 
in which Re represents an OH, SH, SeH or NH(R10) radical, R6 and R10 have the same meanings as in formula (I), by application or adaptation of the methods described in the examples and by X. HUANG, Synthesis, 851-852 (1984), W. C. LUMMA et al., J. Med. Chem., 24, 93-101 (1981) and E. J. JACOBSEN et al., J. Med. Chem., 39, 158-175 (1996).
The derivatives of formula (IX) may be obtained by application or adaptation of the methods described by R. BELCHER et al., J. Chem. Soc., 3846 (1954); B. L. MYLARY, J. Med. Chem., 34, 108-122 (1991); D. W. COMBS et al., J. Med. Chem., 35, 172-176 (1992), W. C. LUMMA et al., J. Med. Chem., 24, 93-101 (1981) and A. V. ZEIGER et al., J. Org. Chem., 42 (3), 542 (1977).
The derivatives of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94 may be obtained by oxidizing a corresponding derivative of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94.
This reaction is generally carried out by means of tert-butyl hydroperoxide and chromic anhydride in aqueous solution, in an inert solvent such as a chlorinated solvent (dichloromethane or chloroform for example), at a temperature close to 20xc2x0 C. Preferably, the nitrogen of the corresponding derivative of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2 is protected beforehand.
The derivatives of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94COxe2x80x94N(R10)xe2x80x94 may be obtained by reacting ethyl glycinate with a derivative of formula: 
in which R6 has the same meanings as in formula (I) and Hal represents a halogen atom and in particular fluorine followed by a reduction-cyclization. When R10 represents an alkyl radical, the alkylation is carried out before the reduction-cyclization.
This reaction is carried out at a temperature between 20xc2x0 C. and the boiling point of the reaction medium. The reduction-cyclization is carried out in a single step by treatment with tin in the presence of hydrochloric acid, in aqueous ethanol, at the boiling point of the reaction medium or with Raney nickel. The alkylation is carried out by the methods described above for the preparation of the compounds of formula (I) for which R2 represents an alkyl radical.
The derivatives of formula (X) may be obtained by application or adaptation of the method described in Chem. Abstr. 113, 233655.
The derivatives of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94COxe2x80x94N(R10)xe2x80x94 may also be obtained accordinglto the following reaction scheme: 
In these formulae, R6 has the same meanings as in formula (I).
The derivatives of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CF2xe2x80x94CH2xe2x80x94 may be obtained by reducing a corresponding derivative of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CF2xe2x80x94CH(OH)xe2x80x94
This reaction is generally carried out by means of triethylsilane and trifluoroacetic acid, at a temperature close to 20xc2x0 C.
The derivatives of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CF2xe2x80x94CH(OH)xe2x80x94 or xe2x80x94CH2xe2x80x94CH(R13)xe2x80x94S in which R13 represents an alkyl radical may be obtained by reducing a derivative of formula: 
in which R6 has the same meanings as in formula (I), xe2x80x94R4xe2x80x94R5xe2x80x94 represents a radical xe2x80x94CF2xe2x80x94CH(OH)xe2x80x94 or xe2x80x94CH(alk)xe2x80x94S and alk represents an alkyl radical.
This reaction is generally carried out by means of the borane-methyl sulphide complex, in toluene, at the boiling point of the reaction medium.
The derivatives of formula (XI) may be obtained according to the following reaction schemes: 
in these formulae, R6 has the same meanings as in formula (I), Et represents ethyl and Boc represents a tert-butoxycarbonyl radical, 
in these formulae, R6 has the same meanings as in formula (I), alk represents an alkyl radical and Boc represents a tert-butoxycarbonyl radical.
The aldehydes (A) may be obtained by application or adaptation of the method described in Chem. Abstr., 107, 39815x.
The derivatives of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain xe2x80x94CH2xe2x80x94CH(R13)xe2x80x94Sxe2x80x94 or xe2x80x94CH2xe2x80x94CH(R9)xe2x80x94CH2xe2x80x94 for which R13 and R9 represent a radical xe2x80x94CH2OH may be obtained by reducing a derivative of formula: 
in which R6 has the same meanings as in formula (I) and R5 represents a sulphur atom or a xe2x80x94CH2xe2x80x94 radical.
This reaction is preferably carried out by means of the borane-dimethyl sulphide complex, in an inert solvent such as toluene or tetrahydrofuran, at the boiling point of the reaction medium.
The derivatives of formula (XII) may be obtained according to the following reaction schemes: 
in these formulae, R6 has the same meanings as in formula (I) and Boc represents a tert-butoxycarbonyl radical. 
in these formulae, R6 has the same meanings as in formula (I).
The derivatives of formula (c) may be obtained as mentioned above for the derivatives of formula (B) using an alkyl bromoacetate instead of alkyl 2-bromopropionate.
The derivatives of formula (D) may be prepared by application or adaptation of the method described in J. Med. Chem., 22 (7), 816-823 (1979).
It is understood for persons skilled in the art that, to carry out the processes according to the invention described above, it may be necessary to introduce groups for protecting amino functional groups so as to avoid side reactions. In particular, the procedure is carried out according to the methods described by T. W. Greene, Protective Groups in Organic Synthesis, A. Wiley Interscience Publication (1981), or by Mc Omie, Protective Groups in Organic Chemistry, Plenum Press (1973). The amino functional groups may, for example, be protected by phthalimido, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, allyloxycarbonyl, vinyloxycarbonyl, trichloroethoxycarbonyl, trichloroacetyl, trifluoroacetyl, chloroacetyl, trityl, benzhydryl, benzyl, allyl, formyl, acetyl or benzyloxycarbonyl radicals or their substituted derivatives or in the form of tert-butyl or methyl carbamates and then regenerated by means of trifluoroacetic acid or hydrochloric acid in tetrahydrofuran or of benzyl carbamates and then regenerated by hydrogenation after having used the process according to the invention.
The reaction mixtures obtained by the various procedures described above are treated according to conventional physical methods (evaporation, extraction, distillation, chromatography and crystallization for example) or conventional chemical methods (formation of salts for example).
The enantiomers of the compounds of formula (I) containing at least one asymmetric site may be obtained by synthesis from chiral precursors or by resolution of the racemates, for example, by chromatography on a chiral column according to W. H. PIRKLE et al., asymmetric synthesis, vol 1, Academic Press (1983).
The compounds of formula (I) in the form of a free base may optionally be converted to addition salts with an inorganic or organic acid, by the action of such an acid in an organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent.
As examples of pharmaceutically acceptable salts, there may be mentioned the addition salts with inorganic or organic acids such as acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulphonate, isethionate, theophyllineacetate, salicylate, methylene-bis-xcex2-oxynaphthoate, hydrochloride, sulphate, nitrate and phosphate.
The compounds of formula (I) exhibit advantageous pharmacological properties. These compounds are anticonvulsants and interfere with glutamatergic transmission and are therefore useful for the treatment or prevention of all ischaemias (such as focal or global ischaemia) following cerebrovascular accidents such as thromboembolic and haemorrhagic stroke, cardiac arrest, arterial hypotension, cardiac, vascular or pulmonary surgery or severe hypoglycaemia. They are also useful in the treatment of the effects caused by anoxia, whether it is perinatal or subsequent to drowning, a high pressure or cerebrospinal lesions. These compounds may also be used to treat or prevent the development of neurodegenerative diseases, of HUNTINGDON""s chorea, of ALZHEIMER""s disease and other dementias, of amyotrophic lateral sclerosis or of other motor neuron diseases, of olivopontocerebellar atrophy and of PARKINSON""s disease. These compounds may also be used against epileptogenic and/or convulsive manifestations, for the treatment of cerebral or spinal traumas, of traumas linked to degeneration of the inner ear (R. PUJOL et al., Neuroreport, 3, 299-302 (1992)) or of the retina (J. L. MONSINGER et al., Exp. Neurol., 113, 10-17 (1991)), of tinnitus, of anxiety (KEHNE et al., Eur. J. Pharmacol., 193, 283 (1991)), of depression (TRULLAS et al., Eur. J. Pharmacol., 185, 1, (1990)), of schizophrenia (REYNOLDS, TIPS, 13, 116 (1992)), of TOURETTE""s syndrome, of hepatic encephalopathies, of sleep disorders, of attention deficit disorders, of disorders of hormonal conditions (excess secretion of GH or LH, secretion of corticosterone), as analgesics (DICKENSON et al., Neurosc. Letters, 121, 263 (1991)), anti-inflammatory agents (SLUTA et al., Neurosc. Letters, 149, 99-102 (1993)), antianorectics (SORRELS et al., Brain Res., 572, 265 (1992)), antimigraine drugs, antiemetics and to treat poisoning by neurotoxins or other substances which are NMDA or AMPA receptor agonists, as well as neurological disorders associated with viral diseases such as viral meningitis and encephalitis, AIDS (LIPTON et al., Neuron 7, 111 (1991)), rabies, measles and tetanus (BAGETTA et al., Br. J. Pharmacol., 101, 776 (1990)). These compounds are also useful for the prevention of, tolerance to and dependency on the symptoms of withdrawal from drugs and alcohol, and of inhibition of addiction to and of dependency on opiates, barbiturates, amphetamine and benzodiazepines. They may also be used in the treatment of deficiencies linked to mitochondrial abnormalities such as mitochrondrial myopathy, LEBER""s syndrome, WERNICKE""s encephalopathy, RETT""s syndrome, homocysteinaemia, hyperprolinaemia, hydroxybutyric-aminoaciduria, saturnine encephalopathy (chronic lead poisoning) and sulphite oxidase deficiency.
The activity of these products as anticonvulsant was determined in mice according to the maximum electroshock method. White CD1 mice are treated intravenously with the test compounds in saline medium 10 minutes before being subjected to an electric shock (75 mA; duration 0.04 second) by means of ocular electrodes. Normally, this shock produces a tonic convulsion in untreated mice, characterized by extension of the limbs. If tonic convulsion does not occur, the animal is considered to be protected. In this test, the compounds of formula (I) have an ED50 of less than or equal to 6 mg/kg.
The activity of these products as antiglutamate was determined on the convulsions induced by glutamate according to a technique inspired by that of I. P. LAPIN, J. Neural. Transmission, 54, 229-238. (1982); the glutamate being injected by the intracerebroventricular route according to a technique inspired by that of R. CHERMAT and P. SIMON, J. Pharmacol. (Paris), 6, 489-492 (1975). Their ED50 is less than 10 mg/kg.
The compounds of formula (I) have a low toxicity. Their LD50 is greater than 15 mg/kg by the IV route in mice.
For medicinal use, the compounds of formula (I) may be used as such or in the form of pharmaceutically acceptable salts, that is to say which are nontoxic at the applicable doses.
Particularly advantageous are the compounds for which
R1 represents a sulphur or selenium atom,
R2 represents a hydrogen atom or an alkyl radical,
xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH(R7)xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CF2xe2x80x94CH(OH)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CO, xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94SOxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94SO2xe2x80x94,
R6 represents a polyfluoroalkyl, polyfluoroalkoxy or polyfluoroalkylthio radical,
R7 represents an alkyl, xe2x80x94CH2OH or xe2x80x94CH2NR11R12 radical,
R8 represents an xe2x80x94NR11R12, xe2x80x94SO2-alk-, xe2x80x94SO-alk- or phenyl radical,
R11 represents a hydrogen atom or an alkyl or acyl radical,
R12 represents a hydrogen atom or an alkyl radical, or alternatively R11 and R12 form with the nitrogen atom to which they are attached a saturated or unsaturated 5- or 6-membered heterocycle optionally containing another heteroatom chosen from nitrogen, oxygen or sulphur.
The following compounds may be mentioned among the particularly advantageous compounds:
2-Imino-8-trifluoromethoxy-5,6-dihydro-2H,4H-thiazolo[5,4,3-ij]quinoline,
2-Imino-8-trifluoromethyl-5,6-dihydro-2H,4H-thiazolo[5,4,3-ij]quinoline,
(R,S)2-Imino-4-methyl-8-trifluoromethyl-5,6-dihydro-2H,4H-thiazolo[5,4,3-ij]quinoline and its enantiomers,
2-Imino-8-trifluoromethoxy-2H,4H-thiazolo[5,4,3-ij]quinolin-6-one,
2-Imino-8-trifluoromethoxy-4,5-dihydro-2H-thiazolo-[3,4,5-de][1,4]benzothiazine 6,6-dioxide,
(R,S)-2-Imino-8-trifluoromethoxy-4,5-dihydro-2H-thiazolo[3,4,5-de][1,4]benzothiazine 6-oxide and its enantiomers,
(R,S)-2-Imino-8-trifluoromethyl-4,5-dihydro-2H-thiazolo[3,4,5-de][1,4]benzothiazine 6-oxide and its enantiomers,
2-Imino-8-trifluoromethyl-4,5-dihydro-2H-thiazolo-[3,4,5-de][1,4]benzothiazine,
(R,S)-2-Imino-6-phenyl-8-trifluoromethyl-5,6-dihydro-2H,4H-thiazolo[5,4,3-ij]quinoline and its enantiomers,
2-Imino-8-trifluoromethoxy-4,5-dihydro-2H-thiazolo-[3,4,5-de][1,4]-benzoxazine,
(R,S)-2-Imino-8-trifluoromethyl-5,6-dihydro-2H,4H-thiazolo[5,4,3-ij]quinoline-4-methanol and its enantiomers,
(R,S)-5,5-Difluoro-6-hydroxy-2-imino-8-trifluoro-methyl-5,6-dihydro-2H,4H-thiazolo[5,4,3-ij]quinoline and its enantiomers,
(R,S)-Ethylmethyl(2-imino-8-trifluoromethyl-5,6-dihydro-2H,4H-thiazolo[5,4,3-ij]quinol-4-ylmethyl)-amine and its enantiomers,
2-Imino-8-trifluoromethyl-5,6-dihydro-2H,4H-selenazolo[5,4,3-ij]quinoline
(R,S)-2-Imino-6-ethylsulphinyl-8-trifluoromethyl-5,6-dihydro-2H,4H-thiazolo[5,4,3-ij]quinoline and its enantiomers,
(R,S)-2-Imino-6-ethylsulphonyl-8-trifluoromethyl-5,6-dihydro-2H,4H-thiazolo[5,4,3-ij]quinoline and its enantiomers and their salts.